The aggregation of peptides and proteins is central to many devastating neurodegenerative disorders, including Alzheimer's disease, Huntington's disease, and the prion diseases. Although amyloid fibrils have long been viewed as the hallmark of Alzheimer's and other neurodegenerative diseases, the oligomers formed by amyloidogenic peptides have begun to emerge as the more important neurotoxic species involved in Alzheimer's and other neurodegenerative diseases. The fibrils adopt layered beta-sheet structures. Although the structures of the oligomers are only beginning to emerge, they appear to also involve beta-sheet formation and may involve layering and related hydrophobic interactions. The development of robust model systems to mimic the structure of amyloid oligomers offers the promise of not only providing insights into the structures and biological activities of amyloid oligomers, but also providing new tools with which to control peptide and protein interactions involving beta-sheet formation. This project will approach the problem of stabilizing small oligomeric beta-sheets by developing interstrand and intersheet crosslinks tailored to stabilize interactions between beta-sheets. These crosslinks will be developed using macrocyclic beta-sheets developed in the PI's laboratory. The macrocyclic beta-sheets form hydrogen-bonded dimers that further self-assemble through hydrophobic interactions to form sandwich-like structures. Intersheet crosslinks will be developed to stabilize the layered structures and control self-assembly. Intrasheet crosslinks will be developed to achieve parallel beta-sheet structures. Macrocyclic beta-sheets containing these crosslinks will be used to mimic the structure of the amyloid beta-peptide dimer. The structures of the mimics of amyloid oligomers will be evaluated by NMR spectroscopy, X-ray crystallography, and other biophysical techniques. The ability of these molecules and molecular assemblies to mimic amyloid beta-peptide oligomers will be evaluated by using oligomer-specific antibodies and neuronal cells to compare their behavior to natural amyloid beta-peptide oligomers. The effect of promising amyloid oligomer mimics on long-term potentiation, long-term synaptic depression, and dendritic spine density at synapses will be studied in mouse hipocampal slices and rat organotypic slices. PUBLIC HEALTH RELEVANCE: Oligomers of peptides and proteins are involved in many devastating neurodegenerative disorders, including Alzheimer's disease and the prion diseases. This proposal seeks to understand and control oligomer formation through the use of chemical model systems. The knowledge that is gained through these studies may eventually lead to new therapies for these diseases.